JAC Advance Access published online on December 1, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh505
© 2004 by The British Society for Antimicrobial Chemotherapy
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1 Swedish Institute for Infectious Disease Control, Department of Bacteriology, S-171 82 Solna, Sweden; Karolinska Institute, Microbiology and Tumour Biology Center, S-171 77 Stockholm, Sweden
* To whom correspondence should be addressed. Objectives: Quinolone resistance in the opportunistic pathogen Pseudomonas aeruginosa is commonly caused by mutations that alter the target molecules DNA gyrase/topoisomerase IV, or cause activation of various efflux systems. We have analysed the effect of quinolone resistance caused by DNA gyrase/topoisomerase IV mutations on bacterial fitness. Methods: Norfloxacin-resistant mutants were isolated and by DNA sequencing the mutations conferring resistance were identified. Mutant fitness was determined by measuring growth rates in vitro. Mutants with reduced growth rates were serially passaged to obtain growth-compensated mutants. The level of DNA supercoiling was determined by isolating plasmid DNA from the susceptible, resistant and compensated mutants and comparing the topoisomer distribution patterns by gel electrophoresis in the presence of chloroquine. Results: Low-level resistance (4-48 mg/L) was caused by single mutations in gyrA or gyrB. Among these strains, three out of eight mutants showed lower fitness, whereas high-level resistant (>256 mg/L) mutants with double mutations in gyrA and parC, parE, nfxB or unknown genes all showed a reduced fitness. Slow-growing resistant mutants with a gyrA mutation had decreased DNA supercoiling. After serial passage in laboratory medium, mutant fitness was increased by compensatory mutation(s) that restored supercoiling to normal levels. The compensatory mutation(s) was not located in any of the genes (gyrAB, topA, parCE, hupB, fis, hupN, himAD or PA5348) that were expected to affect supercoiling. Conclusions: Our results show that ‘no cost’ and compensatory mutations are common in quinolone-resistant P. aeruginosa.
Revised October 15, 2004
Accepted October 19, 2004
Original article
Reduction of the fitness burden of quinolone resistance in Pseudomonas aeruginosa
2 Karolinska Institute, Division of Clinical Bacteriology, Karolinska University Hospital Huddinge, S-141 86 Huddinge, Sweden
Dan I. Andersson, E-mail: Dan.Andersson{at}smi.ki.se
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